Striatal Activation Predicts Differential Therapeutic Responses to Methylphenidate and Atomoxetine

• Published in: Journal of the American Academy of Child and Adolescent Psychiatry Vol. 56; no. 7; pp. 602 - 609.e2
• Main Authors: Schulz, Kurt P., PhD, Bédard, Anne-Claude V., PhD, Fan, Jin, PhD, Hildebrandt, Thomas B., PsyD, Stein, Mark A., PhD, Ivanov, Iliyan, MD, Halperin, Jeffrey M., PhD, Newcorn, Jeffrey H., MD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2017; Elsevier BV
• Subjects: ADHD; Adolescent; Adrenergic Uptake Inhibitors - administration & dosage; Adrenergic Uptake Inhibitors - pharmacology; Antidepressants; Atomoxetine; Atomoxetine Hydrochloride - administration & dosage; Atomoxetine Hydrochloride - pharmacology; Attention Deficit Disorder with Hyperactivity - diagnostic imaging; Attention Deficit Disorder with Hyperactivity - drug therapy; Attention Deficit Disorder with Hyperactivity - physiopathology; Attention Deficit Disorders; Attention deficit hyperactivity disorder; Biological markers; Brain; Brain mapping; Candidates; Caudate nucleus; Caudate Nucleus - diagnostic imaging; Caudate Nucleus - drug effects; Caudate Nucleus - physiopathology; Central Nervous System Stimulants - administration & dosage; Central Nervous System Stimulants - pharmacology; Child; Child & adolescent psychiatry; Cortex; Cortex (motor); Dopamine; Dopamine receptors; Feedback (Response); Female; fMRI; Functional magnetic resonance imaging; Humans; Hyperactivity; Inhibition (Psychology); Magnetic Resonance Imaging; Male; Methylphenidate; Methylphenidate - administration & dosage; Methylphenidate - pharmacology; Motor Cortex - diagnostic imaging; Motor Cortex - drug effects; Motor Cortex - physiopathology; Motor task performance; Neostriatum; Neuroimaging; Neurons; Norepinephrine; Norepinephrine transporter; Number needed to treat; Pediatrics; Psychiatry; Response inhibition; Stimulants; Teenagers; Youth; caudate nucleus; methylphenidate; fMRI; ADHD; atomoxetine
• DOI: 10.1016/j.jaac.2017.04.005
• ISSN: 0890-8567

Objective Methylphenidate has prominent effects in the dopamine-rich striatum that are absent for the selective norepinephrine transporter inhibitor atomoxetine. This study tested whether baseline striatal activation would predict differential response to the two medications in youth with attention-deficit/hyperactivity disorder (ADHD). Method A total of 36 youth with ADHD performed a Go/No-Go test during functional magnetic resonance imaging at baseline and were treated with methylphenidate and atomoxetine using a randomized cross-over design. Whole-brain task-related activation was regressed on clinical response. Results Task-related activation in right caudate nucleus was predicted by an interaction of clinical responses to methylphenidate and atomoxetine ( F1,30  = 17.00; p  < .001). Elevated caudate activation was associated with robust improvement for methylphenidate and little improvement for atomoxetine. The rate of robust response was higher for methylphenidate than for atomoxetine in youth with high (94.4% vs. 38.8%; p  = .003; number needed to treat = 2, 95% CI = 1.31–3.73) but not low (33.3% vs. 50.0%; p  = .375) caudate activation. Furthermore, response to atomoxetine predicted motor cortex activation ( F1,30  = 14.99; p  < .001). Conclusion Enhanced caudate activation for response inhibition may be a candidate biomarker of superior response to methylphenidate over atomoxetine in youth with ADHD, purportedly reflecting the dopaminergic effects of methylphenidate but not atomoxetine in the striatum, whereas motor cortex activation may predict response to atomoxetine. These data do not yet translate directly to the clinical setting, but the approach is potentially important for informing future research and illustrates that it may be possible to predict differential treatment response using a biomarker-driven approach. Clinical trial registration information : Stimulant Versus Nonstimulant Medication for Attention Deficit Hyperactivity Disorder in Children; https://clinicaltrials.gov/ ; NCT00183391.